1. Field of the Invention
The present invention relates to an agent comprising trehalose for preventing or treating vasospasm, cerebral ischemia or cerebral infarction.
2. Description of the Related Art
Subarachnoid hemorrhage (SAH) is a disease in which there is bleeding in subarachnoidal space. Patients with subarachnoid hemorrhage also often develop, for example, consciousness disturbance, possibly resulting in death.
A symptom developing after subarachnoid hemorrhage is cerebral vasospasm. Cerebral vasospasm is a disease wherein constriction of a cerebral vessel develops within two weeks after subarachnoid hemorrhage. Patients with cerebral vasospasm exhibit cerebral ischemia symptom and may go into a vegetable state or even die. However, the action mechanism and the causative substances of cerebral vasospasm are yet to be elucidated. For that reason, there exists a need for studies on the action mechanism and the causative substances of cerebral vasospasm and the development of an agent for treating or preventing cerebral vasospasm.
Oxyhemoglobin is suggested to cause cerebral vasospasm in R. Loch, et. al., “A Review of Hemoglobin and the Pathogenesis of Cerebral Vasospasm” Stroke, Vol. 22, No. 8, pp. 971-982. 1991.
Correlation between HO1 (Heme Oxygenases-1) and cerebral vasospasm is suggested in Minoru Kuroki, et al., “Effect of Vasospasm on Heme Oxygenases in Rat Model of Subarachnoid Hemorrhage”.
Nimodipine, a Ca antagonist, is recommended for prevention of cerebral vasospasm in Mayberg, M. R., et al., “Guidelines for the Management of Aneurismal subarachnoid Hemorrhage” Circulation., Vol. 90, No. 5, pp. 2592-2605, 1994 (Non-Patent Document 1) (p. 2599, left column, lines 11 to 32).
An “agent for treating cerebral vasospasm characterized by comprising activated protein C as the active ingredient” is disclosed in JP-A No. 2000-247904 (Claim 1).
An agent for preventing or treating vasospasm comprising “(2R,4R)-4-methyl-1-[N2((RS)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidinecarboxylic acid, the hydrate or a pharmaceutically acceptable salt thereof as the active ingredient is disclosed in JP-A No. 2000-086518 (Claim 1).
A “cerebral vasospasm inhibitor comprising alacepril as the active ingredient” is disclosed in JP-A No. 11-222439 (Claim 1). Alacepril is a known compound having a chemical name of “1-(D-3-acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine or (S)—N-[1-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-prolyl]-L-phenylalanine”.
An “agent for treating cerebral vasospasm characterized by comprising a thrombomodulin-like protein as the active ingredient” is disclosed in JP-A No. 09-025239 (Claim 1). The thrombomodulin-like protein means thrombomodulin, a peptide having a region of amino acid sequence that is essential for the biological or immunological activity of thrombomodulin, or the analogue thereof. The thrombomodulin-like protein is a protein substance that binds to thrombin, thus inhibiting thrombin's clotting-accelerating action and also accelerating activation of protein C by thrombin significantly.
An “agent for preventing, treating or alleviating cerebral vasospasm comprising 1-ethyl-2-[N-(2-methoxy)benzoyl-N-{2-methoxy-3-(4-octadecyl carbamoyloxy)piperidinocarbonyloxypropoxy}carbonyl]aminomethylpyridinium chloride or a pharmacologically acceptable salt thereof” is disclosed in JP-A No. 08-26994 (Claim 3).
A “cerebral vasospasm inhibitor characterized by comprising Maxadilan exhibiting vasodilating action to mammals” is disclosed in JP-A No. 07-173072 (Claim 1).
An “agent for preventing or treating cerebral vasospasm, comprising at least one peptide selected from calcitonin gene-dependent peptides and vasoactive intestinal polypeptides and urokinase in combination as the active ingredients” is disclosed in JP-A No. 06-116166 (Claim 1). The calcitonin gene-dependent peptide is abbreviated as CGRP and the vasoactive intestinal polypeptide, as VIP.
A thromboxane synthase inhibitor “Sodium Ozagrel Intravenous Infusion” 80 mgJD is sold from Nippon Hexal Corporation. The medicine is said to suppress cerebral vasospasm and alleviates cerebral ischemia and movement disturbance associated with cerebral thrombosis.
As described above, various agents for treating or preventing cerebral vasospasm have been proposed, but there is no highly effective medicine available yet.
On the other hand, vasospasm induces diseases other than those by cerebral vasospasm, such as cerebral ischemia and cerebral infarction. For example, if an abnormal phenomenon occurs on blood vessel such as breakage of blood vessel in case of placement of catheter, transplantation of blood vessels such as formation of bypass blood vessels, and placement of a stent or an embolization coil in addition to a normal surgical operation, it may induce vasospasm. This vasospasm makes difficult the surgical operation, insertion of a catheter, placement of a stent, etc. It is possible to improve the safety of an operation, if the vasospasm during a surgical operation of blood vessels, for example, during bypass blood vessel formation, can be prevented. It is also possible to improve the safety of an operation or placement of a stent, if the vasospasm during insertion of a catheter and before placement of a stent or an embolization coil can be prevented. Accordingly, there exists a need for an agent for preventing the vasospasm associated with a transvascular operation.
Alternatively, tension caused by a vascular transplant, a catheter, a stent or an embolization coil may induce vasospasm. For example, vasospasm caused by coronary artery transplant may cause obstruction of blood vessel and even myocardial infarction. For that reason, there exists a need for an agent for treating vasospasm associated with a vascular transplant operation such as a transvascular operation that breaks blood vessels or applies external force to blood vessels and also for an agent for preventing or treating vasospasm after placement of a catheter, a stent or an embolization coil. That is, prevention of vasospasm after a surgical operation such as vascular transplantation paves the way to prevention of severe diseases such as heart diseases including myocardial infarction. Thus, there is a demand for an agent for treating, preventing, or alleviating vasospasm caused by a surgical operation.
“Use of (−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]-propanedinitrile or a pharmaceutically acceptable salt thereof in production of an agent for treating or preventing vasospasm by coronary artery transplant” is disclosed in Japanese Patent Application National Publication No. 2003-503353.
Development of a slow-release cerebral vasospasm inhibitor for intracerebral implant is also desired. Slow-release cerebral vasospasm inhibitors comprising a water-soluble polymer having a cellulose skeleton and sugars as the slow-release carrier are disclosed, for example, in JP-A No. 7-267880 (Patent Document 2) (Claim 18). It is described in the same document (paragraph [0010]), “Examples of the sugars used include sucrose, lactose, glucose, fructose, maltose, dextrin, trehalose, pullulan and the like. Among them, lactose and glucose are preferable. It is possible to adjust the slow-release velocity by addition of sugars, and the addition in a greater amount leads to increase in release velocity”. Thus in the same document, trehalose is cited as a sugar controlling the drug release velocity of the slow-release carrier water-soluble polymer. However, there is no example actually employing trehalose or no description on the efficacy of trehalose at all. In the same document, there is no description of trehalose's action to treat or prevent vasospasm at all.
Alternatively, a blood circulation improver comprising glycosylated vitamin P as the active ingredient is disclosed in JP-A No. 11-171778 (Claim 1). A blood circulation improver comprising a glycosylated vitamin P as the active ingredient and trehalose additionally is also disclosed in the same document (Claim 5). Disclosed in the same document is that trehalose intensifies the blood circulation-improving action of the glycosylated vitamin P (for example, paragraph [0009]). In the document, the glycosylated vitamin P having blood circulation-improving action is a major agent, and trehalose is described only as an additional agent intensifying the blood circulation-improving action of the glycosylated vitamin P. There is no description of trehalose's action to treat or prevent vasospasm in the same patent document.
Alternatively, JP-A No. 2002-161049 (Patent Document 3 below) discloses a vascular intima-thickening inhibitor comprising epidermal growth factor family as the active ingredients. The paragraph [0031] teaches, “The solid preparation can be prepared as freeze-drying substances by adding an excipient such as mannitol, trehalose, sorbitol, lactose, glucose, maltose, saccharose, starch, or magnesium stearate to epidermal growth factor EGF. It may be powdered.” In other words, trehalose is cited as a diluent for production of the solid preparation. However, trehalose is exemplified only as a diluent, and there is no example actually using trehalose or no description about the efficacy of trehalose at all. The same document does not describe trehalose's action to treat or prevent vasospasm at all.
Patent Document 1: JP-A No. 2000-247904
Patent Document 2: JP-A No. 7-267880
Patent Document 3: JP-A No. 2002-161049
Non-Patent Document 1: Mayberg, M. R., et al., “Guidelines for the Management of Aneurismal subarachnoid Hemorrhage” Circulation., Vol. 90, No. 5, pp. 2592-2605, 1994